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Cortico hippocampal circuit function

Learning and memory formation are basic cognitive functions of the brain. These processes are vital to the survival of an organism and for our own sense of self and individuality.

Our research addresses a fundamental question of neuroscience: How does the brain encode and recall memories and produce adaptive behaviors based on past experience? The entorhinal cortex and hippocampus are interconnected brain areas that support the formation and retrieval of episodic memories, our conscious knowledge of people, places, objects and events.

We want to understand how neural activity in the entorhinal-hippocampal network enables processing and encoding of information about the outside world. While the study of neural circuits in behavior has been underway for decades now, research in my lab will take the overarching perspective of integrating higher brain functions such as learning and memory with the cellular and synaptic mechanisms neurons utilize to modulate their output during salient activity.

We hope that the findings of our research will provide an appreciation for how neural circuits that mediate plasticity at the level of a cell or group of cells can functionally orchestrate adaptive behaviors at the level of the organism.

Reciprocal interactions between the hippocampus and the entorhinal cortex.

My post-doctoral research has focused on mechanisms by which the hippocampal CA1 circuit could integrate entorhinal cortex sensory inputs with information processed within the hippocampus to generate activity dependent changes in the efficacy of synaptic transmission. I have found that one such mechanism is an input-timing-dependent plasticity, ITDP, which utilizes the timing of glutamatergic and GABAergic inputs routed from the entorhinal cortex to modulate coincident activity within the hippocampus and subsequently enhance excitation of CA1 pyramidal neurons in the long-term.

Future studies in my lab will test whether glutamatergic and GABAergic long-range inputs from the hippocampus could similarly modulate local circuit activity in the entorhinal cortex to shape cortical information flow.

This project will involve:

Characterizing the much elusive local circuitry and input connectivity of the entorhinal cortex using anatomical and functional mapping approaches, and

Examining how excitation and inhibition from the hippocampus shapes activity patterns, associational integration and registry of sensory information in the entorhinal cortex with complementary in vitro and in vivo electrical and optical recordings.

Findings of this research will shed light on how our knowledge influences the perception of ongoing experiences and shape the encoding of new versus familiar information.

Variable functional tuning of GABAergic micro circuits.

A major goal of my future research will be to identify the synaptic and circuit-based mechanisms that modulate the dynamics of excitation and inhibition.

The hippocampal CA1 region alone has > 21 different types local GABAergic neurons. These provide a rich substrate for distinct frequency and neuromodulatory tuning by virtue of their physiological properties and molecular makeup. Yet, we know little about how these GABAergic neurons contribute to hippocampal functions such as plasticity or learning behavior. Do GABAergic inputs just act to balance excitation, or do they have specific roles in organizing information flow?

The most basic GABAergic microcircuits include feed-forward and feed-back inhibitory circuits that are either directly driven by incumbent excitatory inputs or recurrently excited by the same neurons they inhibit. Furthermore GABAergic neurons also inhibit other inhibitory neurons to effectively disinhibit information flow. Such disinhibition may occur locally within a certain subregion or remotely through inter-regional long-range projections.

The timing and domains of inhibition are important factors determining how an inhibitory neuron exercises its weight in the circuit. We are interested in understanding how fundamental GABAergic microcircuits participate in sensory experience driven activity and contributes to associational learning.

This project will involve devising new methods to modify and sense GABAergic transmission across the spatio-temporal domains to parse out:

ways in which GABAergic transmission is differentially regulated by specific temporal patterns of activity and neuromodulatory inputs in a behavioral state dependent manner using in vivo electrophysiology and imaging.

how local and long-range GABAergic inputs render neuronal computations at various cellular compartments and how this impacts overall circuit output. We will employ intersectional genetic and optical targeting approaches with electrophysiology and behavioral analysis.

These insights are critical to understand the functional relevance of basic GABAergic circuit motifs that do occur across the brain. We are particularly motivated to apply these insights towards developing ways to manipulate neuronal activity and properties in order to restore functional deficits arising from disruption of the excitation-inhibition balance during debilitating neural disorders such as epilepsy, schizophrenia and depression.